N-(tertiary-aminoalkylmercaptoalkyl) diphenyl-acetamides and their preparation



Patented June 5, 1951 UNITED ATES PATENT OFFICE ALKYL) DIPHENYL-ACETAMIDES AND THEIR PREPARATION- Raymond 0.. Clinton, Albany County, N. Y., as,-

signor to Sterling Drug In'c Wihnington, Del., a corporation of Delaware No Drawing. Application July 3, 1948, Serial No. 37,069

8 Claims. (01. zed-50 1) atoms, including such groups as CH2CH2, CH2CH2CH2 -CH2CH2CH2CH2 and oHl( 1H(oH (2) N (3 (3 (1 piperidyDpropylmercapto) -2-propyl) diphenylacetamide,

CHFGH:

oflnmcnc ONHCH GH2S'CH2CHZCHZN on,

B3 CH2-C a (3) N (3 (2 (2 methyl 1 piperidyD- ethylmercapto) -2-pr0py1) diphenylacetamide,

era-H1 0H, oer-c (4) N (2 (2 diethylaminoethylmercapto) ethyl) diphenylacetamide,

(C(LHORCHCONHCHgOHg-S-CH2CH:N(C3H5)3 2 In practicingmyinvention I prepared my basic amides'by one of two general methods: (a) reactio i of a diphenylace'tyl halide of the formula (CsH aCil-llCQehalogen with the appropriate basic B, Z, and'Y have the meanings specified herein,

above; or (1)) reaction of a lower alkyl ester 01" diphenylacetic acid of the formula,

(CeH5) zcHCOo -(lower alkyl) with the basic amine of the formula;

where B, Z, and Y have the meanings specified hereinabove, preferably in the presence of a basic catalyst, such as sodium or a sodium alkoxide. Whilemethod (b) is preferably run in the presence f a basic catalyst, this method is also operable in the absence of such a catalyst.

In the preparation of the basic amides of my-" invention usin rocedure (a), little or no heat is; needed to carry out the reaction. In fact, prolon ed heating of the sulfur-containing-tertiary-aminoalkylamines with a diphenylacetyl halide may produce mixtures from which no crystallin substance can be obtained. The reaction between the acid halide and the diamine may resultin the deposition of the hydrochloride ina form which resists crystallization, or

v which if crystallized is found to be hygroscopic.

However the sometimes inconvenient physical properties of these hydrochlorides in the solid state-do not preclude their effective preparation and: use in solution, and in fact the high solubility of these hydrochlorides is often advanta eous. Where solid crystalline salts of COX]:- venient-phy sical properties are desired, I' have found the citrates to be suitable. These are prepared by treating a solution of the free basic amide with an equivalent of citric acid monohydrate.

Preparation of the intermediate sulfur c'on taining tertiary-aminoalkylamines are described in the literature by Clinton et al., J. Am. Chem. Soc. 67, 594 (1945) and ibid. 69, 519 (1947).

I found it convenient to isolate and use the basic amides of my invention as the watersoluble citric acid salts or hydrochloric acid addition salts. It is, of course, understood that other Water-soluble salts, such as those derived from other non-toxic organic acids, including tartaric acid, succinic acid, and the like, and other non-toxic inorganic acids, including hydrobromic acid, sulfuric acid, phosphoric acid, and the like, have equivalent therapeutic efficacy and are within the scope of my invention.

Also comprehended by my invention are the quaternary salts of our basic amides, said salts being derived from esters of strong inorganic acids and organic sulfonic acids, and such esters including methyl bromide, ethyl sulfate, n-propyl iodide, benzyl chloride, methyl para-toluenesulfonate, and the like.

The following examples illustrate specific embodiments of the invention:

N (2 (2 diethylaminoethylmercapto)- ethyl)diphenylacetamide.To a mixture of 17.6 g. (0.100 mole) of 2-(2-diethylaminoethylmercapto)ethylamine, 12.6 g. (0.150 mole) of sodium bicarbonate, and 80 ml. ofwater is added, with vigorous stirring, a solution of 27.6 g. (0.12 mole) of diphenylacetyl chloride in 100ml. of chloroform during a period of forty-five minutes. After the mixture has been stirred for one additional hour, the chloroform layer is separated, washed with dilute sodium hydroxide solution and with water, and dried over anhydrous potassium carbonate. Removal of the chloroform by distilling in vacuo yields a viscous colorless oil which readily crystallizes. Two recrystallizations from ethyl acetate-petroleum ether (n-pentane fraction) gives 24.5 g. (62.3%) of N-(2-(2-diethylaminoethylmeroaptc) ethyl)diphenylacetamide as white leaflets, M. P. 56-7 C. The citrate of this amide is formed by treating an acetone solution of the amide with an equivalent quantity of citric acid monohydrate dissolved in acetone. This salt, N (2 (2 diethylaminoethylmercapto)ethyl)- diphenylacetamide citrate, M. P. 80 0., forms as white rosettes.

v Other basic amides are prepared according to the above procedure when other sulfur-containing tertiary-aminoalkylamines are used. Thus,

N (3-(2-dimethylaminoethylmercapto)-2propyl) diphenylacetamide is prepared when the diamine is 3-(2-dimethylaminoethylmercapto) 2- propylamine; N-(3-(3 diethylaminopropylmercapto) propyl) diphenylacetamide is formed when the diamine is 3 (3 diethylaminopropylmercapto) propylamine; and N- (3- (2- (l-piperidyl) ethylmercapto) propyl) diphenylacetamide results when 3-(2-(1 piperidyl)ethylmercapto)propylamine is used.

l In addition, the basic amides of my invention are formed when the appropriate sulfur-containing tertiary-aminoalkylamine is reacted with a lower alkyl ester of diphenylacetic acid. This reaction is carried out by refluxing a petroleum ether (fraction of mixed octanes) solution of equim'olar quantities of the diamine and ester for several hours preferably in the presence of a small amount of sodium, adding an equivalent amount of benzene, washing the resulting mixture with water, drying the same over anhydrous sodium sulfate, removing the solvents by distilling in vacuo, and treating the residual oil as in the above example. In such a manner is obtained N (2 (2 diethylaminoethylmercapto) ethyl) diphenylacetamide citrate from methyl diphenylaoetate and 2-(2-diethylaminoethylmercapto)ethylamine. This preparation can also be carried out using sodium ethoxide as the basic catalyst in place of sodium or in the absence of any basic catalyst.

I claim:

1. A member of the group consisting of a basic amide having the formula where Y and Z are lower alkylene radicals each having 2 to 1 carbon atoms; and B is a member of the group consisting of lower dialkylamino and l-piperidyl groups and non-toxic acid addition and quaternary ammonium salts thereof.

; V 2. N 2- (2-diethylaminoethylmercapto) ethyl) diphenylacetamide citrate.

3. The process of preparing a basic amide having the formula (lower a1kyl)z where Y and Z are lower alkylene radicals each having 2 to 4 carbon atoms.

6. Addition saltswith non-toxic acids of the basic amide of claim 5.

7. N (2 (2 diethylaminoethylmercapto)- ethyl)diphenylacetamide.

8. Addition salts with non-toxic acids oi. the basic amide of claim 7.

RAYMOND 0. CLINTON.

n REFERENCES CITED The followingv references are of record in the file of this patent: j

UNITED STATES PATENTS .Name 7 -Date Miescher et al July 23, 1935 OTHERJREFERENCES,

Clinton et al.: J. Am. Chem. Soc.; vol. 67 (April, 1945), pp. 594-597.

Huber et al.:J. Chem. Soc.; vol. 68 (Feb., 1946), pp. 322-323;

Laskowski et al.: J. Am. Chem. Soc.; vol. 69 (Man. 1947), pp. 519-521. 7.

Number 

2. A N-(2-(2-DIETHYLAMINOETHYLMERCAPTO)ETHYL)DIPHENYLACETAMIDE CITRATE. 